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WHAT'S NEW IN COAGULATION: FEBRUARY 2010

Embolic Protection: Unmet Clinical Need or Unneeded Technology

While the debate continues about whether embolic protection devices are really necessary.Ten years ago, the first embolic protection devices were born, and they have since provided a fertile and lucrative field for start-ups, many of which have been acquired by the large cardiology companies. But for the large companies that now sell the first-generation devices, the field hasn't lived up to its promise, not even in carotid stenting, where the ability to prevent stroke makes the use of these devices most compelling.
Embolic protection devices (EPDs) designed to capture the debris that breaks off during percutaneous revascularization procedures didn't exist 10 years ago, and now they make up a crowded category, particularly for an area whose promise remains largely unfulfilled. All the major cardiovascular companies jumped into the game by acquiring first-generation start-ups offering distal filters and occlusion balloons ( see Exhibit 1), in an effort to capture portions of what was originally seen as a market in excess of half a billion dollars.
What made the original vision of embolic protection devices compelling was not just the size of the market but the potential to expand the use of a variety of existing and emerging percutaneous procedures. This continuing interest can perhaps best be explained by the fact that there is a compelling underlying logic to the notion of using devices to protect against the risk of debris floating upstream to the brain and causing a stroke

Misoprostol may help stop postpartum hemorrhage.

As an alternative to oxytocin, researchers are suggesting that misoprostol may help stop postpartum hemorrhage. Researchers found that "among women who received prophylactic oxytocin in the third stage of labor, misoprostol was noninferior to oxytocin in stopping postpartum bleeding within 20 minutes (89% versus 90% of women)." In a similar trial conducted abroad on "women who did not receive prophylactic oxytocin, both drugs were highly effective, but misoprostol did not benefit as many women (90% versus 96%), and fell short of establishing noninferiority," according to a paper in The Lancet. Still, investigators concluded that "800 µg sublingual misoprostol could be an effective first-line treatment alternative when oxytocin is not available."

Prasugrel "Economically Attractive" Treatment Based on Cost-Effectiveness Analysis

A new cost-effectiveness analysis suggests that prasugrel (Effient, Lilly/Daiichi Sankyo) is an "economically attractive treatment strategy" when compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in patients with acute coronary syndrome (ACS) undergoing planned PCI [1]. After 15 months of treatment with either drug, average total costs were $221-per-patient lower with prasugrel, largely because of a reduction in the rates of rehospitalization following PCI. Prasugrel was also associated with a life expectancy gain of 0.102 years, the result of a decreased rate of nonfatal MI, report investigators.

Antithrombotic Agents and Endoscopic Procedures

The risk of developing a gastrointestinal (GI) hemorrhage during or following a GI endoscopic procedure is rare albeit well recognized. Clearly some procedures have a higher risk potential for bleeding, for example, polypectomy or sphincterotomy. Given the risk potentials, it has been fairly standard practice to withhold antiplatelet agents for a time before the endoscopy and to continue holding these for a defined period following a therapeutic endoscopy.
The use of antiplatelet agents, however, has clear benefit in patients with cardiovascular or neurovascular disease. Withholding these agents for even a short time may have considerable risks -- in particular, for coronary stent thrombosis, myocardial infarct, stroke, and death. Cardiology guidelines recommend dual antiplatelet therapy (aspirin + clopidogrel) for a minimum of 1 month following a bare metal stent and ideally continuing for 12 months. For patients who have a drug-eluting stent, a minimum of 6 months of dual therapy is recommended with extended benefit of continued use for up to 3 years.
Accordingly, in these patients, the risk for a thrombotic event during interruption of therapy must be carefully balanced against the potential risk for GI bleeding. Two recent publications address this balance and make new recommendations for the management of these antithrombotic agents for patients undergoing elective endoscopy. The first article is a guideline from the American Society of Gastrointestinal Endoscopy.[1] The second article is a consensus "white paper" by a writing group appointed from the American College of Cardiology and the American College of Gastroenterology.[2] Although physicians who deal with these patients should carefully review both of these documents, I have highlighted some of the important changes for clinical practice:
1. Diagnostic endoscopy: No clinical trials have demonstrated an increased bleeding incidence for patients taking aspirin or clopidogrel who undergo diagnostic GI endoscopy of any type when no biopsy is performed.
2. In assessing the risk for temporary discontinuation of antiplatelet therapies, it is important to assess the inherent risk of bleeding related to the procedures. High-risk procedures associated with increased bleeding risk include endoscopic polypectomy or mucosal resection, therapeutic enteroscopy, and laser ablation. Furthermore, some procedures are associated with bleeding that may be inaccessible or uncontrollable by endoscopic means. This includes dilation of strictures, percutaneous gastrostomy, fine needle aspirations, or Tru-Cut biopsy.
3. Aspirin should not be stopped at any point if the patient is high risk and aspirin is clearly needed for cardiovascular or neurovascular indications. For high risk procedures, clinicians may elect to stop aspirin or nonsteroidal anti-inflammatory drugs for 5-7 days depending on the underlying indication for the antiplatelet therapy.
4. Clopidogrel can be stopped for a short duration (typically 7-10 days prior to the procedure) if 1 month has elapsed since a bare metal stent procedure. For drug-eluting stents, short-term discontinuance of clopidogrel within 3 months should be avoided, and, ideally, clopidogrel should not be interrupted for the first 6 months. Abrupt cardiac stent thrombosis (which can occur when clopidogrel is withheld or discontinued) is associated with a myocardial infarct rate of 50% and related death rate of approximately 20%. Aspirin should be continued when clopidogrel is held.
5. In patients whose antiplatelet therapy is temporarily interrupted, treatment should be resumed as soon as possible following elective GI endoscopy. Whether a loading dose (600 mg) of clopidogrel is used for the initial dose or the patient is started on a maintenance dose (300 mg) should be gauged by the individual patient level of risk (stent type, time from stenting).

Simple Clinical Decision Rule Aids Management of Clinically Suspected Deep Vein Thrombosis
Clinical Context

Although many patients present to primary care practices with symptoms consistent with lower-extremity DVT, up to 90% of these patients referred to noninvasive testing do not have thrombosis. The authors of the current study previously examined the use of a clinical risk score as well as serum D-dimer testing to help rule out DVT more effectively in primary care. The simple clinical scale assigned 1 point of risk for each of the following factors: male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, and distension of collateral leg veins. A difference in calf circumference of 3 cm or more counted for 2 points, and a positive D-dimer qualitative test was worth 6 points.
Use of this clinical tool was previously demonstrated to effectively rule out over 99% of cases of suspected thrombosis among low-risk adults. The current study seeks to validate the clinical decision rule in primary care practices.
Study Highlights
- Approximately 300 general practitioners referred patients into the study between 2005 and 2007.
- Study participants were consecutive patients from primary care practices with at least 1 of the following 3 lower extremity symptoms: swelling, redness, or pain. Patients younger than 18 years or who were receiving anticoagulant treatment were excluded from study participation.
- All patients completed the clinical decision criteria described above for DVT, including the qualitative capillary D-dimer test. If the clinical decision rule score was 3 or lower, patients were not referred for ultrasonography of the lower extremity, whereas patients with a score of 4 or higher were referred for ultrasonography.
- All patients revisited their primary care clinician at 5 to 9 days after their initial presentation to reevaluate their symptoms. Patients received a questionnaire at 3 months addressing symptoms and signs of DVT.
- The main study outcome was the usefulness of the clinical decision rule plus the D-dimer test in predicting the absence of symptomatic thrombosis (including DVT and pulmonary embolism) at 3 months.
- 1028 patients provided data for study analysis. The mean age of participants was 57.7 years, and 37% were men. 87% and 78% of patients reported leg pain and swelling, respectively. The median duration of symptoms was 5 days.
- 49% of patients had a clinical score of 3 or lower. During 3 months of follow-up, 1.4% of these participants developed venous thromboembolism.
- 49% of patients had a clinical score of 4 or higher. Of these patients, 25% had an ultrasound that was positive for DVT. Among the 374 participants with a normal ultrasound in this group, only 1.1% developed venous thromboembolism during follow-up.
- Neither patient history and physical examination nor D-dimer testing alone was sufficient to rule out DVT. Using only a cutoff of a score of 3 or fewer points on the history and examination portion of the decision tool would miss 9.6% of patients with DVT. Using only a negative D-dimer test as the decision-maker to avoid ultrasonography would miss 3.4% of patients with DVT.
Pearls for Practice
- Clinical risk factors for DVT in the current clinical rule include male sex, active cancer in the last 6 months, surgery in the previous month, absence of leg trauma, distension of collateral leg veins, and a difference in calf circumference of 3 cm or more.
- A simple clinical tool to evaluate the risk for lower extremity DVT safely reduced the number of patients referred to ultrasound by nearly half in the current study.

COX-2 Inhibitor Potential Treatment for Extraabdominal Desmoid Tumors

Meloxicam (Mobic), a cyclooxygenase (COX)-2 inhibitor drug used for arthritis, has shown promise as a treatment for extraabdominal desmoid tumors, according to the results of a small pilot study. The study results, which were published online December 21 in the Journal of Clinical Oncology, showed that of 20 patients treated with meloxicam who were available for evaluation, 19 (95%) had a final status of stable disease or better.
Extraabdominal desmoid tumors are generally sporadic in nature and can occur in virtually any body site, note the authors. However, they are primarily found in the extremities, chest, abdominal wall, and neck. They can be locally aggressive and invasive to surrounding anatomic structures, leading to pain, functional impairment, and deformity.
Management usually involves a multidisciplinary approach that includes surgery and radiation, but these have potential associated morbidities. This has led to investigations of both cytotoxic and noncytotoxic chemotherapy, but because the tumors are rarely fatal, finding a pharmacologic treatment with fewer complications is desirable, according to the authors.
The authors hypothesized, on the basis of previous studies, that COX-2 might be a potential therapeutic target. Experimental in vitro and in vivo research demonstrated decreased cell proliferation in desmoid cell cultures and small tumors when COX-2 was blockaded with pharmacologic agents.
Among the 20 patients evaluated, the researchers observed 1 complete response, 7 partial responses, 11 patients with stable disease, and 1 patient who had progressive disease. Although the 2 patients who discontinued treatment were not included in the evaluation, they had stable disease at the time they stopped the therapy. Patient sex, tumor size, tumor site, follow-up interval, and period of medication were not significant prognostic factors of responsiveness. However, age appeared to play a role; good responders were significantly older than poor responders (P = .0091).
Meloxicam was well tolerated and none of the patients in the final analysis experienced any adverse effects. Of the 2 patients who discontinued treatment, 1 did so because of mild gastritis, and the other was elderly with had a history of cerebral infarction and suffered from intermittent pneumonia and diarrhea.
Baxter may face product-liability suits over tainted heparin.
Baxter International Inc., which recalled its blood thinner heparin amid reports of allergic reactions and deaths in 2008, faces at least 30 lawsuits in Chicago by injured people." Meanwhile, "as many as 300 product-liability complaints may be filed in the Illinois state court, plaintiffs' attorney Allen Schwartz of Kralovec, Jambois & Schwartz said." The manufacturer "began a voluntary recall after...an increase in reports of allergic reactions to injections of the drug, said Erin Gardiner, a company spokeswoman." But, Gardiner noted that "a large number of claims" may not "involve contaminated heparin or in some cases, even Baxter heparin."


New anti-clotting drug performs better than Plavix in study.

Among patients who underwent planned stenting for treatment of acute coronary syndromes, those treated with the investigational antiplatelet agent ticagrelor (Brilinta) had fewer cardiovascular events than patients who received clopidogrel (Plavix)." This "finding emerged from a prespecified subset analysis of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, published online by The Lancet." Researchers found that, "for every 1,000 patients admitted to the hospital with a planned invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in 11 fewer deaths, 13 fewer MIs, and six fewer cases of stent thrombosis. For people with acute coronary syndrome, this very well may replace Plavix." FDA "approval for Brilinta could come late this year, although it's difficult to predict the timing of such decisions,

Statins may reduce stroke risk.

Statins may reduce the risk of stroke, according to a study published in the Journal of the American College of Cardiology. Investigators looked at "data from clinical trials including almost 267,000 participants." The research "showed an overall 12 percent reduction in stroke incidence among those taking statins, with each one percent reduction in total cholesterol predicting a 0.8 percent relative risk reduction of stroke."

FDA says Spiriva may not be linked to increased stroke risk.

Spiriva HandiHaler (inhaled tiotropium bromide), which is used to treat patients with COPD, may not be linked to an increased stroke risk. The "FDA began investigating" the product's "safety last March after" Spiriva's maker "Boehringer reported slightly higher rates of stroke and heart attack for patients using its device, compared with a placebo." However, the agency "now says a recent review of a company-sponsored, 6,000-patient study did not show evidence of increased risk.
Many patients stop taking secondary prevention drugs within two years of stroke.
Many patients stop taking secondary prevention drugs within just two years after suffering a stroke. To prevent new cardiovascular events after stroke, preventive drugs should be used continuously.
But, investigators eventually discovered that "as many as 50% of stroke survivors stop taking secondary-prevention drugs within two years of hospital discharge. About 25% of patients had stopped taking antihypertensives at two years, and almost half had discontinued statin therapy for secondary prevention." In addition, "more than half had quit prescribed warfarin, and more than a third had stopped taking antiplatelet medication.

Update of the Guidelines for Lupus Anticoagulant Detection: F1000 Ranking: "Changes Clinical Behavior"

Changes Clinical Practice: Screening for lupus anticoagulant (LA) should be limited to two tests that represent two different assay principles. The Dilute Russell Viper Venom Time (dRVVT) and Activated Partial Thromboplastin Time (aPTT) should be the tests of choice.
This manuscript updates the guidelines on lupus anticoagulant (LA) detection. Several aspects from patient selection to the test itself are discussed in an attempt to minimise inappropriate test requests for LA, establish some modalities for blood collection and guide physicians on which tests should be performed and how the results should be analysed and interpreted. This article highlights the importance of using laboratory markers in the context of the clinical manifestations/suspicions and not as part of indiscriminate screening.
The authors suggest that LA testing should be limited to those with a significant probability of having antiphospholipid syndrome. Appropriateness to test for LA is graded from low to high in an attempt to avoid the risk of obtaining false-positive results. The authors establish some recommendations for optimal laboratory detection of LA, from blood collection to establishment of the cut off point and interpretation of the results. It is well recognised that there is no single test sensitive for all LAs, although the authors acknowledge that using more than two screening tests increases the rate of false positivity. The recommendation is to perform two different tests, being the Dilute Russell Viper Venom Time (dRVVT) believed to be the most specific and the Activated Partial Thromboplastin Time (aPTT) sensitive enough for the detection of LA. Other tests are less reliable and/or non-standardised and their use is discouraged. These guidelines are relevant to anyone working in the field of autoimmune diseases, particularly lupus and antiphospholipid syndrome. Some evidence supports the fact that dRVVT is the most robust and specific test for detecting LA. Any aPTT test could be the second choice because of its sensitivity.

Pleuritic Chest Pain, Thrombophilia Predict Pulmonary Embolism

Now the rules leave out certain variables that could help raise or lower suspicion, according to the authors. In their analysis, two of the strongest predictors of PE were a history of non-cancer-related thrombophilia and pleuritic chest pain.
The goal of the study was to assess the predictive value of information that physicians commonly collect from patients with suspected PE, information that has not been formally validated, Dr. Jeffrey A. Kline from Carolinas Medical Center, Charlotte, North Carolina, told Reuters Health by email.
Dr. Kline and his colleagues examined 13 "implicit variables" that are commonly used to initiate, delay, or obviate testing for PE, yet have not been validated or incorporated into existing prediction rules. The implicit variables were compared with 12 "explicit variables" that are included in prediction rules.
In a paper published online January 4th in the Annals of Emergency Medicine, the researchers report that they used data from 7940 emergency room patients who had formal testing for pulmonary embolism, as ordered by 477 different clinicians. Eventually, 568 patients (7.2%) met standard criteria for pulmonary embolism or deep vein thrombosis.
Among the implicit variables, a history of non-cancer-related thrombophilia (OR, 1.99), pleuritic chest pain (OR, 1.53), and family history of venous thromboembolism (OR, 1.51) were positively associated with venous thromboembolism, while female gender (OR, 0.57), current smoking (OR, 0.59), and substernal chest pain (OR, 0.58) were negative predictors. The presence of tachypnea and patient perception of dyspnea were marginally associated with an increased risk of venous thromboembolism.
Four of the implicit variables commonly used to support formal PE testing proved to be statistically nonsignificant, including pregnancy or postpartum state, sudden onset of symptoms, obesity, and history of treated but currently inactive malignancy.
Among the 12 explicit variables, 3 (hemoptysis, trauma within 4 weeks, and shock index greater than 1.0) were not statistically associated with venous thromboembolism. Of the remaining 9 variables, the strongest predictors were patient history of venous thromboembolism (OR, 2.90) and unilateral leg swelling (OR, 2.60), surgery in the last 4 weeks (OR, 2.27), current estrogen use (OR, 2.31), and hypoxemia (OR. 2.10).

Amphastar alleges FDA conflict of interest in heparin investigation.

The Los Angeles Times (1/21, Zajac) reports on a "new appeal in a conflict-of-interest controversy involving the Food and Drug Administration's handling of the deadly heparin contamination crisis of 2008." In announcing it would "appeal the FDA's rejection of a complaint," Amphastar Pharmaceuticals Inc. "alleged that Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, had a conflict of interest." Amphastar questions the inclusion of scientists from Momenta Pharmaceuticals on a taskforce with Woodcock tasked with identifying the culprit of the heparin contamination. Momenta is a rival of Amphastar, also applying for FDA approval of a generic form of heparin. FDA spokeswoman Karen Riley defended the taskforce saying that the agency "pulled together the team of experts, including Woodcock, under emergency conditions. 'People were dying. We had to find an answer,' Riley said."

New Variant Linked to Platelet Response and Bleeding Events With Clopidogrel

A new analysis of genetic data has identified yet another polymorphic variant of the CYP2C19 gene that influences platelet aggregation and bleeding events among clopidogrel-treated patients who underwent PCI. Individuals with a copy of the CYP2C19*17 allelic variant had a significantly reduced platelet response and significantly greater risks of bleeding compared with individuals without the *17 polymorphism, although there was no difference in rates of stent thrombosis with the variant.The results of the study are published online January 18, 2010 in Circulation.
Conversion to Its Active Metabolite
Clopidogrel is a prodrug that requires metabolization and activation to its active metabolite by the hepatic cytochrome P450 system. The metabolization of clopidogrel is achieved with a number of different isoenzymes, including CYP2C19, which is believed to play a dominant role in the process. Previous studies, have shown that a common loss-of-function CYP2C19*2 variant is associated with a blunted response to clopidogrel and affects platelet aggregation. The purpose of this study, was to determine whether the CYP2C19*17 variant, which has been linked to increased transcriptional activity and extensive metabolization of CYP2C19 substrates, leads to an enhanced response to clopidogrel and differences in clinical outcomes.
In total, 1524 patients undergoing PCI after pretreatment with 600 mg of clopidogrel were studied. Following the procedure, patients were discharged with a dual antiplatelet treatment regimen of aspirin 100 mg twice daily and clopidogrel 75 mg once daily. Of the patients, 622 were carriers of at least one *17 allele, including 546 patients who were heterozygous (wt/*17) and 76 who were homozygous (*17/*17) for the polymorphism.
Testing showed that the lowest ADP-induced platelet-aggregation values were seen in patients carrying both mutant alleles. Of the 622 patients who had at least one copy of the *17 variant, platelet aggregation values were significantly lower than individuals who did not have any copies of the *17 polymorphism.
Carriers of the CYP2C19*17 variant were also at a significantly greater risk of bleeding than those without the polymorphism, with the highest risk observed among individuals homozygous for the *17 variant (p=0.01 for trend).There are 25 known polymorphic variants of the CYP2C19 gene, with the frequency varying among different ethnic groups

Very Low Birthweight Male Babies Have Higher Risk for Intraventricular Bleeding

Among very low birth weight (VLBW) infants, the risk of intraventricular hemorrhage (IVH) is higher in males, and male babies are also more likely to have severe IVH, new research shows. These conclusions are based on data from nearly 105,000 VLBW infants born in the U.S. between 1997 and 2004. All of the infants were free of major congenital abnormalities.
In general, male infants "are more susceptible to adverse outcomes of prematurity, including death, respiratory distress syndrome, and bronchopulmonary dysplasia. There is also evidence from a small cohort study that males are at greater risk for IVH than are females.According to a report in the February issue of Pediatrics, 15.9% of male infants had IVH compared with 13.6% of female infants (OR, 1.15, p < 0.001).
After controlling for significant confounding variables, the investigators found that in addition to having a higher incidence of IVH, boys were more likely to have severe IVH (38% vs. 32.7%, OR, 1.18, p < 0.004). Body weight appeared to influence the association between gender and IVH, the findings suggest. Specifically, the link between male gender and IVH was stronger in babies weighing 1000 to 1499 g than in those who weighed <1000 g (OR: 1.19 vs. 1.14, p = 0.006).
Pediatrics 2010;125:e333-e339.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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